In the case of injury, whether a consequence of surgery or from an accident or a mishap, wounds do not heal completely and this often leads to additional health complications. Of the reasons for this is because in would injuries, multiple biochemical pathways are activated and thus in order to achieve complete healing, simultaneous modulation of multiple biological responses is needed, in a similar way in many disease sates, several different cell and protein types are affected. To treat the disease effectively, all of the affected cell types must be treated. This involves developing methods and materials that can effectively modulate multiple biological responses.
As one example, a recent study by the American Academy of Orthopedic Surgeons estimates that over 500,000 bone-grafting surgeries are performed annually. By 2030, an overall incident increase of 600% is predicted in the United States alone. Standard clinical grafting practices to repair bone-tissue damage include autografting, allografting and xenografting. However, these procedures often result in incomplete healing and lead to additional health complications in patients. To overcome these problems, researchers are developing new bone-tissue engineering strategies such as using natural and synthetic materials as scaffolds for repair. A number of these engineered scaffolds are currently available for clinical uses. However, a well-accepted, versatile and clinically-proven scaffold is yet to be fully realized.
Because of the multi-faceted problems associated with wound injuries, it would be ideal for interventions to treat inflammation, thrombosis, infection, and wound healing in one treatment that can be easily applied in a variety of field settings—emergency response, battlefield, hospitals, homes and clinics. An ideal treatment would inhibit multiple consequences of injury, such as inflammation, thrombosis, and infection, without causing systemic effects. At the same time, it would be judicious if the treatment also promoted wound healing processes. In these ways, a method is needed that can modulate multiple cellular responses.
Such as strategy requires (1) the identification of suitable therapeutic agent(s) with short biological half-lives and (2) designer polymers that act as sophisticated drug carriers. The therapeutic agents used to develop these materials should be at least in part agents that are already involved in normal homeostasis. For example, the endothelial cells that line all blood vessel walls have a number of bound therapeutic agents and bioagents that are released from the surface of the endothelial cells that are responsible for maintaining normal homeostasis within the blood. As a result, synthetic materials and methods that have features that replicate the function of the normal endothelium are more likely to provide the ultimate route to safely modulating biological responses. As such, the materials and methods described herein leverage the biological properties of naturally occurring biogents in synthetic materials to control biological responses in order to treat a wide range of diseases or to prevent biofouling or treat injuries associated with a variety of medical devices where localized control of function is only at the fluid-delivery agent interface where action is targeted.
To date, two major classes of synthetic polymers have been explored as materials in these types of applications. The first class includes synthetic biodegradable polymers such as polylactide (PL), polyglycolide (PG), poly(lactide-co-glycolide) (PLGA) and poly(ε-caprolactone)(PC). These materials are formed into nanoscaffolds using the process of electrospinning. The resulting scaffolds have diameters between 50-500 nm (similar to the size of many naturally occurring fibrous components such as collagen within ECM), high porosities (up to 80%), and large surface areas for cell attachment, bone in-growth, and nutrient transport, making the materials a suitable ECM analogue for tissue engineering applications. However, because these polymers have relative low hydrophilicities and lack cellular recognition, cell affinity to the scaffold to promote osteointegration is significantly diminished. In the end, the scaffold results in poor cell adhesion, migration, proliferation and differentiation.
A second class of biodegradable materials that have been studied for these applications include polysaccharide-grafted polymers. Investigators have demonstrated that these materials have adequate mechanical properties (tensile strength and bending strength) to support tissue growth over natural materials such as collagen. Moreover, the polysaccharides materials have improved cell compatibility and structural integration with many cell adhesion molecules and matrix glycoproteins as compared to the PL and PLGA polymers. For example, chitosan, a naturally available polysaccharide, is structurally similar to glycosaminoglycans (GAGs) present within bones and possesses a number of osteophilic advantages including biocompatibility and biodegradability. Similarly, dextran, a homopolymer of glucose with predominantly α-(1→6) linkages has been investigated as a material for tissue scaffolds due to its relative biocompatibility and degradability. The high surface tension of these polysaccharide materials due to their polycationic nature have caused challenges in fabricating nanofibers using electrospinning methods. As a result, composites materials of chitosan have been prepared by blending the polysaccharide with various fiber-forming polymers such as poly(vinyl alcohol), poly(ethylene oxide), poly(vinyl pyrrolidone), poly(ε-caprolactone) and poly(L-lactic-co-ε-caprolactone). The composite materials were then successfully spun into nanofibers. The resulting nanofibers, however had inconsistence mechanical and cell affinities in regions of the scaffold.
Although the synthetic and polysaccharide-derived materials have demonstrated an alternative to autografting, allografting and xenografting, the materials still do not possess all of the requisite biological properties of an ideal material to modulate cellular responses. Specifically, the materials cause activation of the coagulation cascade and provoke the immune response system (i.e., cause inflammation). As shown in FIG. 1, the tissue healing cascade begins immediately following injury and goes through four stages: hemostasis, inflammation, proliferation, and remodeling. First, the coagulation cascade is activated and platelets aggregate around exposed collagen leading to a fibrin clot matrix that leads to eventual healing. Subsequently, a variety of other factors are released including cytokines, platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-β) during the inflammatory phase. As a result of this release, neutrophils, macrophages, and lymphocytes are stimulated. The proliferative phase follows and is marked by epithelialization, angiogenesis, and fibroblast growth and results in new connective tissue. In the final phase collagen is cross-linked and scar maturation results. If any part of the healing cascade is perturbed, fibrosis and chronic ulcers may result.